The hypotheses that form the basis of this proposal are that the amyloid beta-proteln (Abeta) causes degeneration of vascular smooth muscle cells in cerebral blood vessels which leads to abnormal expression and cellular accumulation of the amylold beta-proteln precursor (AbetaPP) and a concomitant increase in cellular carboxyl terminal AbetaPP fragments and soluble Abeta. Apolipoprotein E (ApoE) can also contribute to increased expression of AbetaPP in cerebrovascular smooth muscle cells. Therefore, Abeta and ApoE can induce subsequent formation of additional Abeta in cerebral blood vessel walls further contributing to the cerebral amylold anglopathy (CAA) In disorders Including Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). The proposed studies will provide important information on how Abeta, AbetaPP and cerebrovascular smooth muscle cells potentially interact to play key roles in the initiation and spread of the cerebrovascular pathology associated with CAA in disorders including AD and HCHWA-D. The specific objectives of this proposal are to investigate the effects of Abeta peptides and ApoE on the expression and processing of AbetaPP that accompanies the degeneration of cultured human smooth muscle cells from cerebral blood vessels. Investigations will also be performed to compare the effects of soluble and aggregated forms of Abeta peptides as well as normal and HCHWA-D Abeta peptides on cellular degeneration and expression and processing of AbetaPP in the cultured cerebrovascular smooth muscle cells. We also plan to investigate the mechanisms by which Abeta induces cell death in cerebrovascular smooth muscle cells. Studies will be performed to determine if these combined effects of Abeta peptides are observed in other cultured cerebrovascular and peripheral vascular cells. This may provide insight as to why the cerebrovascular pathology of AD and related disorders is restricted to cerebral blood vessels. Within the framework of the program project, parallel studies on the effects of Abeta peptides on the expression and processing of AbetaPP in cultured neurons will be conducted in collaboration with Dr. Cotman and his colleagues as described in his proposal. These studies will be important to determine if different or similar Abeta-induced pathologic mechanisms occur in cerebrovascular smoo4h muscle cells and neurons. In addition, future investigations will be conducted in collaboration with Dr. Glabe and coworkers concerning the differential uptake and degradation of the different length Abeta peptides by the cultured HLSM cells. These studies coincide with our long term goals to better understand the expression and processing of APP leading to Abeta formation and deposition that contributes to the hallmark cerebrovascular pathology in AD, HCHWA-D and related disorders.